Project Summary/Abstract Healthcare-acquired infections (HAIs) have received significant attention in recent years. An increasing number of mandates have been enacted at the federal and state levels to force the implementation of HAI-prevention strategies, and considerable resources are now devoted to supporting them without a clear template for how to evaluate their clinical and economic ramifications. Surgical site infections (SSI) are among the most common HAIs and result in significant morbidity, mortality, and health care costs. Use of prophylactic antibiotics directed against skin organisms is a standard of care process for preventing SSI. An increasing prevalence of methicillin-resistant S. aureus (MRSA) carriage has complicated the traditional approach of using a -lactam (e.g. cephalosporin) for antimicrobial prophylaxis because it does not work against MRSA. In patients known to have MRSA colonization or infection, vancomycin is recommended for surgical prophylaxis. However, it is not clear whether vancomycin should be used alone or in addition to a -lactam drug. The use of vancomycin alone as surgical prophylaxis has significant downsides, including inability to prevent Gram-negative (e.g. E. coli) infections and selecting for vancomycin resistance. The comparative and cost effectiveness of MRSA screening-directed vancomycin surgical prophylaxis vs. universal vancomycin for high- risk surgeries has also not been established. Thus, there are critical gaps in knowledge to fully inform policies and best practices for SSI prevention. The main aims of this proposal include: 1) Conduct a retrospective cohort study to determine the risk of SSI in MRSA positive and MRSA negative patients undergoing surgical procedures, stratified by surgical prophylaxis regimen and other risk factors such as age, type of surgery, and ASA classification to test the hypothesis that pre-operative nasal MRSA status is an effect modifier of the association between receipt of vancomycin surgical prophylaxis and SSI risk; 2) Evaluate the comparative effectiveness of vancomycin alone vs. vancomycin plus a -lactam as surgical prophylaxis in prevention of SSI to test the hypothesis that the combination regimen is more effective in preventing SSI than vancomycin alone; and 3) Evaluate the comparative and cost-effectiveness of pre-operative screening followed by directed vancomycin surgical prophylaxis vs. universal vancomycin for high-risk surgeries to test the hypothesis that the cost efficiency of screening-directed surgical prophylaxis compared to universal vancomycin surgical prophylaxis depends on the MRSA prevalence in the screened population. We will utilize existing national VA databases to conduct a retrospective cohort study of patients undergoing surgeries that are assessed for specific performance measures by the Surgical Care Improvement Project's External Peer Review Program (EPRP). We will use regression and Markov modeling to evaluate comparative effectiveness and cost-effectiveness of MRSA- screening directed surgical prophylaxis approaches and regimens. The findings will be implemented in coordination with the MRSA Prevention Initiative Program Office.